Idiopathic Pulmonary Fibrosis (IPF)

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  • IDIOPATHIC PULMONARY FIBROSIS, 2017:

    PATHOGENESIS AND NOVEL THERAPEUTIC TARGETS

    Bruce D. Uhal Department of Physiology Michigan State University

    East Lansing, Michigan

  • Disclosures

    Paid Consultantships: last date:GlaxoSmithKline 2017Actelion Pharm. Ltd 2007

  • Definition: a chronic progressive and inevitably fatal* lung disease

    Idiopathic Pulmonary Fibrosis (IPF)

    NORMAL IPF

  • Definition: a chronic progressive and inevitably fatal* lung disease

    *

    Idiopathic Pulmonary Fibrosis (IPF)

    NORMAL IPF

    Recently, pirfenidone and nintedanib, 2 antifibrotic drugs, have been proven to be effective in slowing disease progression and are now approved as treatments in the US and Europe.

  • Definition: a chronic progressive and inevitably fatal* lung disease distortion of the lungs architecture with excess ECM unknown etiology 6.8-16cases/100,000 median survival ~3yr

    Diagnostic Criteria:clinical history: exclusion of occupational exposures etc

    typical HRCT pattern of Usual Interstitial Pneumonia

    if HRCT non diagnostic: SLB to confirm UIP histology

    Idiopathic Pulmonary Fibrosis (IPF)

    NORMAL IPF

  • Definition: a chronic progressive and inevitably fatal* lung disease distortion of the lungs architecture with excess ECM unknown etiology 6.8-16cases/100,000 median survival ~3yr

    Diagnostic Criteria:-clinical history: exclusion of occupational exposures etc-typical HRCT pattern of Usual Interstitial Pneumonia

    if HRCT non diagnostic: SLB to confirm UIP histology

    Idiopathic Pulmonary Fibrosis (IPF)

    NORMAL IPF

  • Definition: a chronic progressive and inevitably fatal* lung disease distortion of the lungs architecture with excess ECM unknown etiology 6.8-16cases/100,000 median survival ~3yr

    Diagnostic Criteria:-clinical history: exclusion -typical HRCT pattern of Usual Interstitial Pneumonia:

    if HRCT non diagnostic: SLB to confirm UIP histology

    Idiopathic Pulmonary Fibrosis (IPF)

    NORMAL IPF

    Subpleural & basal reticular opacitiesTraction bronchiectasisHoneycomb changes (cystic airspaces thick walls 0.3-1.0cm)

  • Definition: a chronic progressive and inevitably fatal* lung disease distortion of the lungs architecture with excess ECM unknown etiology 6.8-16cases/100,000 median survival ~3yr

    Diagnostic Criteria:-clinical history: exclusion of occupational exposures etc-typical HRCT pattern of Usual Interstitial Pneumonia

    if HRCT non diagnostic: SLB to confirm UIP histology

    Idiopathic Pulmonary Fibrosis (IPF)

    NORMAL IPF

  • Definition: a chronic progressive and inevitably fatal* lung disease distortion of the lungs architecture with excess ECM unknown etiology 6.8-16cases/100,000 median survival ~3yr

    Diagnostic Criteria:-clinical history: exclusion of occupational exposures etc-typical HRCT pattern of Usual Interstitial Pneumonia

    if HRCT non diagnostic: SLB to confirm UIP histology

    Idiopathic Pulmonary Fibrosis (IPF)

    NORMAL IPF

  • Injury

    Alveolitis

    Derangements of Parenchyma

    Loss of functionalalv.-capillary units

    Honeycomb Lung

    Pathogenesis of IPF-Traditional View:

    IPF viewed as aninflammatory diseaseFrom: Crystal, Ferrans and Basset, Ch7.8.1 The Lung:Scientific Foundations, 1991

    Traditional View

  • Injury

    Alveolitis

    Derangements of Parenchyma

    Loss of functionalalv.-capillary units

    Honeycomb Lung

    Pathogenesis of IPF-Traditional View:

    IPF viewed as aninflammatory diseaseFrom: Crystal, Ferrans and Basset, Ch7.8.1 The Lung:Scientific Foundations, 1991

    Elephant in the room:

    Antiiflammatory/Immunosuppressive Approaches do not work!

    Traditional View

  • The failure of antiinflammatory/immunosuppressive clinical trials:

    AJRCCM 190:867-878, 2014

  • The failure of antiinflammatory/immunosuppressive clinical trials:

    An Alarming Press ReleaseWells AU et al.Eur.Resp.J.39:805-6, 2012

    AJRCCM 190:867-878, 2014

    Triple Therapy prednisone azathioprene +NAC

  • Arguments Against the Inflammation Hypothesis:Selm

    Selman et al. Am J RespCrit Care Med 165:1205-8, 2002 Gauldie et al. Respir Res 2002; 3: 3-11. al.

    Anti-inflammatories/immunosuppressives dont work

    Inflammation does not correlate with stage or outcome

    Inflammation is not required for the fibrotic response

    Inflammation is not a prominent histopathologic finding

    SO, what IS critical in IPF?

    IPF - Pathogenesis Theory

  • Arguments Against the Inflammation Hypothesis:Selm

    Selman et al. Am J RespCrit Care Med 165:1205-8, 2002 Gauldie et al. Respir Res 2002; 3: 3-11. al.

    Anti-inflammatories/immunosuppressives dont work

    Inflammation does not correlate with stage or outcome

    Inflammation is not required for the fibrotic response

    Inflammation is not a prominent histopathologic finding

    SO, what IS critical in IPF?

    IPF - Pathogenesis Theory

    SO, what IS critical in IPF?

  • Histological Features of the IPF Lung:

    F1000 Research 2016, 5(F1000 Faculty Rev):1046

    Spatial heterogeneity: subpleural/paraseptal fibrosis vs. spared parenchyma

    Temporal heterogeneity: active fibroblast foci, ECM deposition & paucity of inflammatory infiltrate vs. regions of normal lung histo

  • Histological Features of the IPF Lung:

    F1000 Research 2016, 5(F1000 Faculty Rev):1046

    Spatial heterogeneity: subpleural/paraseptal fibrosis vs. spared parenchyma

    Temporal heterogeneity: active fibroblast foci, ECM deposition & paucity of inflammatory infiltrate vs. regions of normal lung histo

    IPF

    CTL

    PICROSIRIUS RED

    Uhal et al. AmJPhysiol275:L1192-9, 1998

  • Histological Features of the IPF Lung:

    Annu Rev Pathol. 2014; 9:157-179

    Key features of UIP: 1. fibroblastic foci -at the edge between fibrotic vs normal lung

    -deposit collagens (myofibroblasts)

    -Presence & number predict mortality in IPF! Nicholson et al. AJRCCM 166:173177, 2002

  • Histological Features of the IPF Lung:

    Annu Rev Pathol. 2014; 9:157-179

    Key features of UIP: 1. fibroblastic foci -at the edge between fibrotic vs normal lung

    -deposit collagens (myofibroblasts)

    -Presence & number predict mortality in IPF! Nicholson et al. AJRCCM 166:173177, 2002

    Fibroblast Myofibroblast TGF-1

    collagen SMA

  • Histological Features of the IPF Lung:

    Annu Rev Pathol. 2014; 9:157-179

    Key features of UIP: 1. fibroblastic foci -at the edge between fibrotic vs normal lung

    -deposit collagens (myofibroblasts)

    -Presence & number predict mortality in IPF! Nicholson et al. AJRCCM 166:173177, 2002

    Fibroblast Myofibroblast TGF-1

    collagen SMA

  • Histological Features of the IPF Lung:

    Annu Rev Pathol. 2014; 9:157-179

    Key features of UIP: 1. fibroblastic foci -at the edge between fibrotic vs normal lung

    -deposit collagens (myofibroblasts)

    -Presence & number predict mortality in IPF! Nicholson et al. AJRCCM 166:173177, 2002

    2. Reactive-appearing epithelium -cuboidal

    -primarily type II-like

    -previously described as hyperplastic

  • Persistent and unrepaired epithelial damage (apoptosis)

    Proliferation and accumulation of fibroblast/myofibroblasts

    Thickening of alveolar wall by deposition of collagens I & III

    Obliteration of the alveolar space.

    Histological Features of the IPF Lung:

    CTL

    IPF

    IPFISEL

    The Hyperplastic Alveolar Epithelium is now known to be:dividing and dying (by apoptosis) simultaneously

    Uhal et al. Alveolar epithelial cell death adjacent to underlying myofibroblasts in advanced fibrotic human lung. Am. J. Physiol. 275:L1192-L1199, 1998.

  • Lung Fibrogenesis Theory: Early evidence for the Severity of Epithelial Injury Hypothesis lung explant studies Witschi, Haschek, Adamson, Bowden 1979-1990

    BHT, O2

    epith. repair

    Upshot: failure of reepithelialization fibrosis in the presence or the absence of blood

  • ANTIFIBROTIC FUNCTIONS OF THE EPITHELIUM:

    Normal Alveolar Epithelium:

    BM

    III

    Barrier~2,000Ohm

    Surfactant surface T immunomod.Antioxidant Def.

    AM

    Soluble Factors Growth factors (e.g. EGF, FGFs) Growth inhibitors (PGE2)

    Proteases uPA(degrade fibrin) MMPs (interstit. collagenases)

  • ANTIFIBROTIC FUNCTIONS OF THE EPITHELIUM :

    Denuded Epithelium:

    BM

    capillary

    BarrierCollapse

    AM Proteases uPA = fibrinolysis MMPsint = collagen

    fibrin

    Lost/damaged type II cells = Surfactant surface T immunomod. Antioxidant Def.

    EGF

    PGE2

    +

    Upshot Epith. death releases fibroblasts from inhibitions

  • Persistent and unrepaired epithelial damage (apoptosis)

    Proliferation and accumulati